This invention relates to a process for the preparation of matrix metalloproteinase inhibitors and to intermediates useful in the process.
Matrix metalloproteinases are a class of extracellular enzymes such as collagenase, stromelysin, and gelatinase which are believed to be involved in tissue destruction which accompanies a number of diseases including arthritis and cancer. There is, therefore, a continuing need for compounds which are inhibitors of matrix matalloproteinase.
The instant invention discloses a synthesis of metalloproteinase inhibitors from ((4S)-2-oxo-1,3-oxazolidin-4-yl)methyl 4-methylbenzenesulfonate (Sibi, M. P., Rutherford, D., Sharma, R. J Chem. Soc. Perkin Trans. 1994, 13, 1, 1675). Although an efficient synthesis of this compound has been reported, racemization occurs during the sequence, causing a reduction in the enantiomeric excess of the final product. This invention discloses a method for the preparation of ((4S)-2-oxo-1,3-oxazolidin-4-yl)methyl 4-methylbenzenesulfonate which significantly reduces racemization.
In one embodiment of the instant invention is disclosed a process for preparing a compound of formula (3) 
wherein
R1 is selected from the group consisting of hydrogen, an amino protecting group, and xe2x80x94OR2;
R2 is hydrogen or a hydroxy protecting group;
L1 is xe2x80x94Oxe2x80x94 or xe2x80x94N(R3)xe2x80x94, wherein R3 is hydrogen or an amino protecting group; and
X is O or S, the process comprising:
(a) reacting a compound of formula (2) 
xe2x80x83wherein
R4 is a carboxyl protecting group, with a reducing agent to provide a first reaction mixture; and
(b) adjusting the pH of the first reaction mixture to about 2 to about 6; and
(c) isolating the compound of formula (3).
In a preferred embodiment the compound of formula (3) is (4R)-4-(hydroxymethyl)-1,3-oxazolidin-2-one.
Another embodiment of the instant invention comprises reacting a compound of formula (1) 
a base, and a reagent selected from the group consisting of phosgene, thiophosgene, triphosgene, carbonyldiimidazole, thiocarbonyldiimidazole, and a dialkyl carbonate.
Another embodiment of the instant invention comprises a process for preparing a compound of formula (5-a) 
or a compound of formula (5-b) 
wherein
Q1 is selected from the group consisting of halide, methanesulfonate, and trifluoromethanesulfonate;
Y is nitrogen or C(H);
R6 is selected from the group consisting of alkoxy, alkoxyalkyl, alkyl, aminosulfonyl, aminosulfonylalkyl, aryl, arylalkyl, cyano, cyanoalkyl, halo, haloalkyl, (heterocycle)oxy, (heterocycle)oxyalkyl, hydroxy, hydroxyalkyl, phenylalkoxy, phenylalkoxyalkyl phenoxy, phenoxyalkyl, perfluoroalkoxy, perfluoroalkoxyalkyl, perfluorothioalkoxy, perfluorothioalkoxyalkyl, sulfinyl, sulfinylalkylsulfonyl, sulfonylalkyl, thioalkoxy, and thioalkoxyalkyl; and
L2 is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, the process comprising:
(a) activating the hydroxyl of the compound of formula (3) 
(b) reacting the product of step (a), a compound of formula (4) 
xe2x80x83and base to provide the compound of formula (5-a) 
(c) optionally oxidizing the product of step (b); and
(d) optionally reacting the product of step (b) or step (c) and a compound of formula (6) 
xe2x80x83wherein
Q2 is selected from the group consisting of trialkylstannanes, boronic acid, boronic esters, magnesium halides, zinc halides, and silyl(alkyl)cyclobutanes, and a coupling catalyst.
In a preferred embodiment the compound of formula (5-a) is
(4R)-4-((4-bromophenoxy)methyl)-1,3-oxazolidin-2-one and the compound of formula (5-b) is
(4R)-4-(((4xe2x80x2-(trifluoromethoxy)(1,1xe2x80x2-biphenyl)-4-yl)oxy)methyl)-1,3-oxazolidin-2-one.
Another embodiment of the instant invention comprises a process for preparing a compound of formula (5-c) 
the process comprising:
(a) reacting a compound of formula (7) 
xe2x80x83wherein
R4 is alkyl, a compound of formula (4) 
xe2x80x83and base to provide a compound of formula (8) 
(b) optionally reacting the product from step (a) and an oxidant;
(c) reacting the product of step (a) or step (b), hydrogen, and a hydrogenation catalyst to provide a compound of formula (9) 
(d) reacting the product from step (c) and base to provide a compound of formula (10) 
(e) reacting the product from step (d) and a compound of formula H2NOR2, or a salt thereof, wherein
R2 is a hydroxyl protecting group, under dehydrating conditions to provide a compound of formula (11) 
(f) reacting the product of step (e) under Mitsunobu conditions to provide a compound of formula (12) 
(g) reacting the product from step (f) and base to provide a compound of formula (13) 
xe2x80x83and
(h) reacting the product from step (g) and azide under dehydrating conditions.
In a preferred embodiment the compound of formula (5-c) is
(5R)-1-(benzyloxy)-5-((4-bromophenoxy)methyl)-2-imidazolidinone.
Another embodiment of the instant invention comprises a process for preparing a compound of formula (15) 
the process comprising:
(a) reacting a compound of formula (5) 
xe2x80x83and base.
In a preferred embodiment the compound of formula (15) is selected from the group consisting of
(2S)-2-amino-3-((4xe2x80x2-(trifluoromethoxy)(1,1xe2x80x2-biphenyl)-4-yl)oxy)-1-propanol,
(2S)-2-amino-3-(4-bromophenoxy)-1-propanol, and
(2R)-2-((benzyloxy)amino)-3-(4-bromophenoxy)-1-propanamine.
Another embodiment of the instant invention comprises a process for preparing of a compound of formula (20), 
or a salt thereof, wherein
R7 and R8, together with the atoms to which they are attached, form a heterocycle selected from the group consisting of 5,5-dimethyl-1,3-oxazolidine-2,4-dionyl; 1-methyl-2,4-imidazolidinedionyl; 1,5,5-trimethyl-2,4-imidazolidinedionyl; 2,4-imidazolidinedionyl; 5,5-dimethyl-2,4-imidazolidinedionyl; 1,2-dimethyl-1,2,4-triazolidine-3,5-dionyl; 4,4-dimethyl-2,6-piperidinedione; 8-azaspiro(4.5)decane-7,9-dionyl; 3a,6-dihydro-1H-benzo(de)isoquinoline-1,3(2H)-dionyl; 2,4(1H,3H)-quinazolinedionyl; 1-methyl-2,4(1H,3H)-pyrimidinedionyl; and 1,1-dioxo-1,2-benzisothiazol-3(2H)-onyl, the process comprising:
(a) reacting a compound of formula (15-a) 
xe2x80x83and a compound of formula R9xe2x80x94CHO, wherein
R9 is optionally substituted aryl, to provide a compound of formula (16) 
(b) reacting the product of step (a) and a compound of formula (17) under Mitsunobu conditions 
xe2x80x83to provide a compound of formula (18) 
(c) reacting the product of step (b) and an oxaziridine forming agent to provide a compound of formula (19) 
(d) reacting the product of step (c) and a compound of formula H2NOR2, or a salt thereof, and base; and
(e) optionally deprotecting the product of step (d).
In a preferred embodiment the compound of formula (20) is selected from the group consisting of
3-((2S)-2-(hydroxyamino)-3-((4xe2x80x2-(trifluoromethoxy)(1,1xe2x80x2-biphenyl)-4-yl)oxy)propyl)-5,5-dimethyl-2,4-imidazolidinedione and
3-((2S)-3-(4-bromophenoxy)-2-(hydroxyamino)propyl)-5,5-dimethyl-2,4-imidazolidinedione.
Another embodiment of the instant invention comprises a process for preparing of a compound of formula (20-b) 
or a salt thereof, the process comprising:
(a) reacting the compound of formula (20-a) 
the coupling catalyst, and the compound of formula (6) 
In a preferred embodiment the compound of formula (20-b) is
3-((2S)-2-(hydroxyamino)-3-((4xe2x80x2-(trifluoromethoxy)(1,1xe2x80x2-biphenyl)-4-yl)oxy)propyl)-5,5-dimethyl-2,4-imidazolidinedione.
Another embodiment of the instant invention comprises a process for preparing of a compound of formula (20-c) 
or a salt thereof, the process comprising:
(a) reacting a compound of formula (15-b) 
xe2x80x83and a compound of formula (21) 
xe2x80x83to provide a compound of formula (22) 
xe2x80x83and
(b) reacting the product from step (a) and acid.
In a preferred embodiment the compound of formula (20-c) is
3-((2R)-2-((benzyloxy)amino)-3-(4-bromophenoxy)propyl)-5,5-dimethyl-2,4-imidazolidinedione.
Another embodiment of the instant invention comprises a process for preparing a compound of formula (23) 
the process comprising:
(a) N-formylating the compound of formula (20); and
(b) optionally deprotecting the product of step (a).
In a preferred embodiment the compound of formula (23) is selected from the group consisting of
(1S)-2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-1-(((4xe2x80x2-(trifluoromethoxy)(1,1xe2x80x2-biphenyl)-4-yl)oxy)methyl)ethyl(hydroxy)formamide and
benzyloxy((1R)-2-(4-bromophenoxy)-1-((4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)methyl)-ethyl)formamide.
Another embodiment of the instant invention comprises a process for preparing a compound of formula (23-b) 
the process comprising:
(a) reacting a compound of formula (23-a) 
xe2x80x83the coupling catalyst, and the compound of formula (6) 
xe2x80x83and
(b) optionally deprotecting the product of step (a).
In a preferred embodiment the compound of formula (23-b) is selected from the group consisting of
4-(((2R)-2-((benzyloxy)(formyl)amino)-3-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-propyl)oxy)-4xe2x80x2-(trifluoromethoxy)-1,1xe2x80x2-biphenyl.
Another embodiment of the instant invention comprises a process for preparing a compound of formula (23-b) 
the process comprising:
(a) reacting a compound of formula (1) 
xe2x80x83a base, and a reagent selected from the group consisting of phosgene, thiophosgene, triphosgene, carbonylduimidazole, thiocarbonyldiimidazole, and a dialkyl carbonate to provide a compound of formula (2); 
(b) reacting the product of step (a) with a reducing agent to provide a compound of formula (3); 
(c) activating the hydroxyl of the product of step (b);
(d) reacting the product of step (c) with base and a compound of formula (4) 
xe2x80x83to provide a compound of formula (5-a), 
(e) optionally oxidizing the product of step (d);
(f) reacting the product of step (d) or step (e), a coupling catalyst, and a compound of formula (6) 
xe2x80x83to provide a compound of formula (5-b), 
(g) reacting the product of step (f) with base to provide a compound of formula (15), 
(h) reacting the product of step (g) with a compound of formula R9xe2x80x94CHO, to provide a compound of formula (16), 
(i) reacting the product of step (h) with a compound of formula (17) 
xe2x80x83to provide a compound of formula (18) 
(j) reacting the product of step (i) and an oxaziridine forming agent to provide a compound of formula (19) 
(k) reacting the product of step (j) with H2NOR2, or a salt thereof, and base to provide a compound of formula (20-b); 
(l) N-formylating the product from step (k) to provide a compound of formula (23-b); 
xe2x80x83and
(m) optionally deprotecting the product of step (1).
Another embodiment of the instant invention comprises a process for the preparation of a compound of formula (23-b) 
the process comprising:
(a) reacting a compound of formula (1) 
xe2x80x83a base, and a reagent selected from the group consisting of phosgene, thiophosgene, triphosgene, carbonyldiimidazole, thiocarbonyldiimidazole, and a dialkyl carbonate, to provide a compound of formula (2); 
(b) reacting the product of step (a) with a reducing agent to provide a compound of formula (3); 
(c) activating the hydroxyl of the product of step (b);
(d) reacting the product of step (c) with base and a compound of formula (4) 
xe2x80x83to provide a compound of formula (5-a), 
(e) optionally oxidizing the product of step (d);
(f) reacting the product of step (e) with base to provide a compound of formula (15), 
xe2x80x83wherein
R5 is Q1;
(g) reacting the product of step (f) with a compound of formula R9xe2x80x94CHO to provide a compound of formula (16), 
xe2x80x83wherein
R5 is Q1;
(h) reacting the product of step (g) with a compound of formula (17) 
xe2x80x83to provide a compound of formula (18) 
wherein R5 is Q1;
(i) reacting the product of step (h) with an oxaziridine forming agent to provide a compound of formula (19) 
xe2x80x83wherein
R5 is Q1;
(j) reacting the product of step (i) with H2NOR2, or a salt thereof, and base to provide a compound of formula (20); 
xe2x80x83wherein
R5 is Q1;
(k) reacting the product of step (j) with a coupling catalyst and a compound of formula (6) 
xe2x80x83to provide a compound of formula (20), 
(l) N-formylating the product from step (k) to provide a compound of formula (23) 
(m) optionally deprotecting the product of step (1).
Another embodiment of the instant invention comprises a process for the preparation of a compound of formula (23) 
the process comprising:
(a) reacting a compound of formula (7) 
xe2x80x83a compound of formula (4) 
xe2x80x83and base to provide a compound of formula (8) 
(b) optionally oxidizing the product from step (a);
(c) hydrogenating the product of step (a) or step (b) to provide a compound of formula (9) 
(d) reacting the product from step (c) with base to provide a compound of formula (10) 
(e) reacting the product from step (d) with H2NOR2 or a salt thereof, wherein R2 is a a hydroxyl protecting group, under dehydrating conditions to provide a compound of formula (11) 
xe2x80x83wherein
R2 is a hydroxyl protecting group;
(f) reacting the product of step (e) under Mitsunobu conditions to provide a compound of formula (12) 
xe2x80x83wherein
R2 is a hydroxyl protecting group;
(g) reacting the product from step (f) with base to provide a compound of formula (13) 
(h) activating the product from step (g) with azide to provide a compound of formula (5-c); 
xe2x80x83wherein
R2 is a hydroxyl protecting group;
(i) reacting the product from step (h) with base to provide a compound of formula (15) 
xe2x80x83wherein
R1 is xe2x80x94OR2;
R2 is a hydroxyl protecting group;
R5 is Q1; and
L1 is xe2x80x94NHxe2x80x94;
(j) reacting the product from step (i) with a compound of formula (21) 
xe2x80x83to provide a compound of formula (22) 
xe2x80x83wherein
R2 is a hydroxyl protecting group;
(k) reacting the product from step (j) with acid to provide a compound of formula (20-c) 
xe2x80x83wherein
R2 is a hydroxyl protecting group;
(l) N-formylating the product from step (k) to provide a compound of formula (23) 
xe2x80x83wherein
R2 is a hydroxyl protecting group;
(m) reacting the product from step (l) with a coupling catalyst and a compound of formula (6) 
to provide a compound of formula (23) 
wherein
R2 is a hydroxyl protecting group R5 is 
and
(n) deprotecting the product of step (m).
Detailed Description of The Invention
This invention relates to processes for the preparation of matrix metalloproteinase inhibitors and to intermediates which are useful in these processes of preparation. The following terms have the meanings specified.
The term xe2x80x9calkoxy,xe2x80x9d as used herein, refers to an alkyl group connected to the parent group through an oxygen atom.
The term xe2x80x9calkoxyalkyl,xe2x80x9d as used herein, refers to an alkyl group to which is attached at least one alkoxy group.
The term xe2x80x9calkyl,xe2x80x9d as used herein, refers to a monovalent straight or branched chain saturated hydrocarbon having one to six carbons.
The term xe2x80x9calkylsulfinyl,xe2x80x9d as used herein, refers to an alkyl group connected to the parent group through a sulfinyl group.
The term xe2x80x9calkylsulfonyl,xe2x80x9d as used herein, refers to an alkyl group connected to the parent group through a sulfonyl group.
The term xe2x80x9camino,xe2x80x9d as used herein, refers to xe2x80x94NH2 or a derivative thereof formed by independent replacement of one or both hydrogens thereon by a substituent selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, and an amino protecting group.
The term xe2x80x9camino protecting group,xe2x80x9d as used herein, refers to selectively removable groups which protect amino groups against undesirable side reactions during synthetic procedures and includes all conventional amino protecting groups. Examples of amino groups include optionally substituted acyl groups such as trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, para-nitrobenzylcarbonyl, ortho-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl, para-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, 1-adamantyloxycarbonyl, and 8-quinolyloxycarbonyl; optionally substituted arylalkyl groups such as benzyl, diphenylmethyl, and triphenylmethyl; optionally substituted arylthio groups such as 2-nitrophenylthio and 2,4-dinitrophenylthio; optionally substituted alkyl sulfonyl and optionally substituted arylsulfonyl groups such as methanesulfonyl, and para-toluenesulfonyl; optionally substituted dialkylaminoalkylidene groups such as N,N-dimethylaminomethylene; optionally substituted arylalkylidene groups such as benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, and 2-hydroxy-1-naphthylmethylene; optionally substituted nitrogen-containing heterocyclic alkylidene groups such as 3-hydroxy-4-pyridylmethylene; optionally substituted cycloalkylidene groups such as cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, and 3,3-dimethyl-5-oxycyclohexylidene; optionally substituted diarylalkylphosphoryl and optionally substituted diarylalkylphosphoryl groups such as diphenylphosphoryl and dibenzylphosphoryl; optionally substituted oxygen-containing heterocyclic alkyl groups such as 5-methyl-2-oxo-2H-1,3-dioxol-4-yl-methyl; and optionally substituted silyl groups such as trimethylsilyl, triethylsilyl, and triphenylsilyl.
The term xe2x80x9caminosulfonyl as used herein, refers to an amino group connected to the parent group through a sulfonyl group.
The term xe2x80x9caryl,xe2x80x9d as used herein, refers to a mono or bicyclic carbocyclic ring system having at least one aromatic ring. Aryl groups are exemplified by phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, and indenyl.
The term xe2x80x9caryl,xe2x80x9d as used herein, also includes compounds of formula 
wherein Y* is xe2x80x94C(O)xe2x80x94 or xe2x80x94(CH2)vxe2x80x94, wherein v is 1 or 2; and Z* is xe2x80x94CH2xe2x80x94 or xe2x80x94Oxe2x80x94. The aryl groups of this invention can be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkoxy, alkyl, halo, and thioalkoxy.
The term xe2x80x9carylalkyl,xe2x80x9d as used herein, refers to an alkyl group to which is attached at least one aryl group.
The term xe2x80x9cbase,xe2x80x9d as used herein, refers to a reagent capable of accepting protons during the course of a reaction. Examples of bases include carbonates such as potassium carbonate, potassium bicarbonate sodium carbonate, sodium bicarbonate, and cesium carbonate; halides such as cesium fluoride; phosphates such as potassium phosphate, potassium dihydrogen phosphate, and potassium hydrogen phosphate; hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; trialkylamines such as triethylamine and diisopropylamine; heterocyclic amines such as imidazole, pyridine, pyridazine, pyrimidine, and pyrazine; bicyclic amines such as DBN and DBU; and hydrides such as lithium hydride, sodium hydride, and potassium hydride. The base chosen for a particular conversion depends on the nature of the starting materials, the solvent or solvents in which the reaction is conducted, and the temperature at which the reaction is conducted.
The term xe2x80x9ccarbonyl,xe2x80x9d as used herein, refers to xe2x80x94C(xe2x95x90O)xe2x80x94.
The term xe2x80x9ccarboxaldehyde,xe2x80x9d as used herein, refers to xe2x80x94CHO.
The term xe2x80x9ccarboxy,xe2x80x9d as used herein, refers to xe2x80x94CO2H.
The term xe2x80x9ccarboxyl protecting group,xe2x80x9d as used herein, refers to selectively removable groups which protect hydroxyl groups against undesirable side reactions during synthetic procedures and includes all conventional carboxyl protecting groups. Examples of carboxyl groups include optionally substituted alkyl groups such as methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, and tert-butyl; aryl groups such as phenyl, and naphthyl; optionally substituted arylalkyl groups such as benzyl, diphenylmethyl, triphenylmethyl, para-nitrobenzyl, para-methoxybenzyl, and bis(para-methoxyphenyl)methyl; optionally substituted acylalkyl groups such as acetylmethyl, benzoylmethyl, para-nitrobenzoylmethyl, para-bromobenzoylmethyl, and para-methanesulfonylbenzoylmethyl; optionally substituted oxygen-containing heterocyclic groups such as 2-tetrahydropyranyl and 2-tetrahydrofuranyl; optionally substituted haloalkyl groups such as 2,2,2-trichloroethyl; optionally substituted alkylsilylalkyl groups such as 2-(trimethylsilyl)ethyl; optionally substituted acyloxyalkyl groups such as acetoxymethyl, propionyloxymethyl, and pivaloyloxymethyl; optionally substituted nitrogen-containing heterocyclic groups such as phthalimidomethyl and succinimidomethyl; optionally substituted cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; optionally substituted alkoxyalkyl groups such as methoxymethyl, methoxyethoxymethyl, and 2-(trimethylsilyl)ethoxymethyl; optionally substituted arylalkoxyalkyl groups such as benzyloxymethyl; optionally substituted alkylthioalkyl groups such as methylthiomethyl and 2-methylthioethyl; optionally substituted arylthioalkyl groups such as phenylthiomethyl; optionally substituted alkenyl groups such as 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, and allyl; and optionally substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl.
The term xe2x80x9ccoupling catalyst,xe2x80x9d as used herein, refers to palladium complexes which enhance the rate of biaryl couplings. Examples of catalysts include palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), Pd2Cl2(dba), and PdCl2.CH2Cl2. Each of these catalysts can be used with an additive such as triphenylphosphine, triphenylarsine, or a trialkylphosphine such as tributylphosphine optionally present.
The term xe2x80x9ccyano,xe2x80x9d as used herein, refers to xe2x80x94CN.
The term xe2x80x9ccyanoalkyl,xe2x80x9d as used herein, refers to an alkyl group to which is attached at least one cyano group.
The term xe2x80x9ccycloalkyl,xe2x80x9d as used herein, refers to a saturated cyclic alkyl group having three to six carbons.
The term xe2x80x9ccycloalkylalkoxy,xe2x80x9d as used herein, refers to an alkoxy group to which is attached at least one cycloalkyl group.
The term xe2x80x9ccycloalkylalkyl,xe2x80x9d as used herein, refers to an alkyl group to which is attached at least one cycloalkyl group.
The terms xe2x80x9chaloxe2x80x9d or xe2x80x9chalide,xe2x80x9d as used herein, refer to F, Cl, Br, or I.
The term xe2x80x9chaloalkyl,xe2x80x9d as used herein, refers to an alkyl group to which is attached at least one halide.
The term xe2x80x9cheterocycle,xe2x80x9d as used herein, refers to five- or six-membered saturated or unsaturated rings having one, two, or three heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The nitrogen and sulfur heteroatoms can be optionally oxidized, and the nitrogen heteroatoms can be optionally quaternized. The heterocycles of the instant invention are attached through a carbon atom in the ring. Representative heterocycles include pyrrolidinyl, piperidinyl, pyrazinyl, pyrazolyl, pyridazinyl morpholinyl, piperazinyl, thiomorpholinyl, pyridyl, pyrimidinyl, quinolyl, furyl, benzofuryl, thienyl, thiazolyl, pyrimidyl, indolyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, 1,2,3-oxadiazolyl, thienyl, triazolyl, 1,3,4-thiadiazolyl, and tetrazolyl.
The term xe2x80x9c(heterocycle)oxy,xe2x80x9d as used herein, refers to a heterocycle attached to the parent group through an oxygen atom.
The term xe2x80x9c(heterocycle)oxyalkyl,xe2x80x9d as used herein, refers to an alkyl group to which is attached at least one (heterocycle)oxy group.
The term xe2x80x9chydroxy,xe2x80x9d as used herein, refers to xe2x80x94OH.
The term xe2x80x9chydroxy protecting group,xe2x80x9d as used herein, refers to selectively introducible and movable groups which protect hydroxyl groups against undesirable side reactions during synthetic procedures. Examples of hydroxyl protecting groups include optionally substituted acyl groups such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-(phenylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphonio)ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, and benzoyl; optionally substituted alkyl groups such as methyl, tert-butyl, 2,2,2-trichloroethyl, and 2-trimethylsilylethyl; optionally substituted alkenyl groups such as as 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, and allyl; optionally substituted arylalkyl groups such as benzyl, para-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, and triphenylmethyl; oxygen-containing and sulfur-containing heterocyclic groups such as tetrahydrofuryl, tetrahydropyranyl, and tetrahydrothiopyranyl; optionally substituted alkoxy and optionally substituted alkylthioalkyl groups such as methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, and 1-ethoxyethyl; alkylsulfonyl; optionally substituted arylsulfonyl groups such as methanesulfonyl, and para-toluenesulfonyl; and optionally substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl.
The term xe2x80x9chydroxyalkyl,xe2x80x9d as used herein, refers to an alkyl group to which is attached at least one hydroxy group.
The term xe2x80x9cmethine,xe2x80x9d as used herein, refers to xe2x95x90C(H)xe2x80x94.
The term xe2x80x9cMitsunobu conditions,xe2x80x9d as used herein, refers to treatment of an alcohol with a diazo compound such as DIAD or DEAD and a triarylphosphine such as triphenylphosphine or a trialkylphosphine such as tributylphosphine.
The term xe2x80x9cpharmaceutically acceptable salt,xe2x80x9d as used herein, refers to salts which are suitable for use in contact with tissue without undue toxicity, irritation, or allergic response and are commensurate with a reasonable benefit/risk ratio. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting a basic group with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, sulfate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, para-toluenesulfonate and undecanoate. Basic nitrogen-containing groups can also be quatemized with alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; and arylalkyl halides such as benzyl and phenethyl bromides. Examples of acids employed to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric and organic acids as oxalic, maleic succinic, and citric.
Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxylic acid-containing group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary, or tertiary amine. Pharmaceutically acceptable salts include cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts and nontoxic quaternary ammonia and amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, and ethylamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.
The term xe2x80x9cpharmaceutically acceptable prodrugs,xe2x80x9d as used herein, refers to prodrugs and zwitterionic forms of the compounds which are suitable for contact with tissue without undue toxicity, irritation, allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
The term xe2x80x9cphenoxy,xe2x80x9d as used herein, refers to a phenyl group connected to the parent group through an oxygen atom.
The term xe2x80x9cphenoxyalkyl,xe2x80x9d as used herein, refers to an alkyl group to which is attached at least one phenoxy group.
The term xe2x80x9cphenylalkoxy,xe2x80x9d as used herein, refers to to an alkoxy group to which is attached at least one phenyl group.
The term xe2x80x9cphenylalkoxyalkyl,xe2x80x9d as used herein, refers to an alkyl group to which is attached at least one phenylalkoxy group.
The term xe2x80x9cperfluoroalkoxy,xe2x80x9d as used herein, refers to a perfluoroalkyl group attached to the parent group through an oxygen atom.
The term xe2x80x9cperfluoroalkyl,xe2x80x9d as used herein, refers to an alkyl group in which all of the hydrogen atoms have been replaced with fluoride atoms.
The term xe2x80x9cperfluoroalkoxyalkyl,xe2x80x9d as used herein, refers to an alkyl group to which is attached at least one perfluoroalkoxy group.
The term xe2x80x9cperfluorothioalkoxy,xe2x80x9d as used herein, refers to a perfluoroalkyl group attached to the parent group through a sulfur atom.
The term xe2x80x9cperfluorothioalkoxyalkyl,xe2x80x9d as used herein, refers to an alkyl group to which is attached at least one perfluorothioalkoxy group.
The term xe2x80x9cprodrug,xe2x80x9d as used herein, refers to compounds which are rapidly transformed in vivo to parent compounds such as, for example, by hydrolysis in blood.
The term xe2x80x9creducing agent,xe2x80x9d as used herein, refers to reagents capable of converting protected carboxylic acids to alcohols. Examples of reducing agents include borane-dimethylsulfide, borane-tetrahydrofuran, and sodium borohydride.
The term xe2x80x9csulfinyl,xe2x80x9d as used herein, refers to xe2x80x94S(O)xe2x80x94.
The term xe2x80x9csulfonyl,xe2x80x9d as used herein, refers to xe2x80x94SO2xe2x80x94.
The term xe2x80x9cthioalkoxy,xe2x80x9d as used herein, refers to an alkyl group attached to the parent molecular group through a sulfur atom.
The term xe2x80x9cthioalkoxyalkyl,xe2x80x9d as used herein, refers to an alkyl group to which is attached at least one thioalkoxy group.
Asymmetric centers exist in the compounds of the invention. The invention contemplates stereoisomers and mixtures thereof. Individual stereoisomers of compounds are prepared by synthesis from starting materials containing the chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, or direct separation of the enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or are made by the processes described herein and resolved by techniques well-known in the art.
Chiral purity (percent enantiomeric excess (ee)) was determined by chiral HPLC (Chiralcel OD) by comparing the enantiomeric purity of a compound from a reaction mixture to a mixture of the same enantiomer in known enantiomeric excess.
Yields of compounds in solution were determined by HPLC by comparing the amount of product in solution to solutions of known concentrations of that product.
Percentages obtained by HPLC analyses were determined by peak area calculations.
All of the processes of the invention can be conducted as continuous processes. The term xe2x80x9ccontinuous process,xe2x80x9d as used herein, refers to the conduction of steps in without isolation of intermediates.
The formylation process used in the synthesis of Example 1N is that described in pending U.S. application Ser. No. 09/539,950, filed on the same day herewith, incorporated herein by reference.
Abbreviations
Abbreviations which have been used in the descriptions of the scheme and the examples that follow are: DBN for 1,5-diazabicyclo[4.3.0]non-5-ene; DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene; dba for dibenzylideneacetone; DIAD for diisopropyl azodicarboxylate; DEAD for diethyl azodicarboxylate; THF for tetrahydrofuran; dppf for diphenylphosphinoferrocene; DMF for dimethylformamide; DME for dimethoxyethane; DMSO for dimethylsulfoxide; BINAP for 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl; DCC for 1,3-dicyclohexylcarbodiimide; DIC for 1,3-diisopropylcarbodiimide; HOBT for 1-hydroxybenzotriazole hydrate; EDCI for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; PyBOP benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate; NMM for N-methylmorpholine; NMP for 1-methyl-2-pyrrolidinone; MTBE for methyl tert-butyl ether; m-CPBA for 3-chloroperoxybenzoic acid; and DPPA for diphenylphosphoryl azide.
Synthetic Processes
The processes and compounds and of the instant invention will be better understood in connection with the following synthetic schemes. The compounds can be prepared by a variety of processes, and representative processes are shown in Schemes 1-9. The groups R1-R9, L1, L2, X, and Q1 are defined previously. It will be readily apparent to one skilled in the art that the selective protection and deprotection steps, as well as the order of the steps themselves, can be carried out in varying order, depending on the nature of R1-R9, L1, L2, X, and Q1, to successfully complete the syntheses shown below. 
As shown in Scheme 1, compounds of formula (1) can be converted to compounds of formula (2) (X is O or S) by treatment of the former with an acylating agent and base. Representative acylating agents include phosgene, triphosgene, carbonyldiimidazole, dialkyl carbonates (for X is O), thiophosgene and thiocarbonyldiimidazole (for X is S). Representative bases include triethylamine, diisopropylethylamine, pyridine, and imidazole.
Solvents used in these reactions include dichloromethane, carbon tetrachloride, 1,2-dichloroethane, and chloroform, although dialkyl carbonates can themselves be used as solvents. The reaction temperature is about xe2x88x9210xc2x0 C. to about 100xc2x0 C. and depends on the method chosen. Reaction times are typically about 0.5 to about 24 hours. In a preferred embodiment, compounds of formula (1) in dichloromethane at 0xc2x0 C. are treated with triphosgene and triethylamine and stirred for 7 hours to provide compounds of formula (2).
Conversion of compounds of formula (2) to compounds of formula (3) can be accomplished by treatment of the former with a reducing agent such as sodium borohydride, lithium aluminum hydride, sodium triacetoxy-borohydride, and lithium tri-tert-butoxyaluminum hydride. Solvents used in these reactions include ethanol, methanol, THF, and diethyl ether. The reaction temperature is about xe2x88x9278xc2x0 C. to about 35xc2x0 C. and depends on the process chosen. Reaction times are typically 1 to 24 hours. In a preferred embodiment, compounds of formula (2) in ethanol at 0xc2x0 C. are treated with sodium borohydride and stirred for 5 hours. The reaction is quenched to a pH of between to provide compounds of formula (3). 
As shown in Scheme 2, compounds of formula (3) can be converted to compounds of formula (5-a) by activation of the hydroxyl group of the former followed by treatment with compounds of formula (4) and base. Activation of the hydroxyl group can be accomplished by treatment with an acylating or sulfonating agent and base. Representative acylating and sulfonating agents include para-toluenesulfonyl chloride, benzenesulfonyl chloride, trifluoroacetic anhydride, and methanesulfonyl chloride. Examples of bases include pyridine, imidazole, diisopropylethylamine, and triethylamine. Solvents used in these reactions include dichloromethane, chloroform, THF, and methyl tert-butyl ether. The reaction temperature is about xe2x88x9210xc2x0 C. to about 50xc2x0 C. and depends on the process chosen. Reaction times are typically about 1 to about 24 hours. The products can then be treated with compounds of formula (4) (L2 is O or S; Q1 is halide, methanesulfonate, or para-toluenesulfonate) and base to provide compounds of formula (5-a). Representative bases include potassium carbonate, sodium carbonate, lithium hexamethyldisilazide, and lithium diisopropylamide. Examples of solvents used in these reactions include acetonitrile, water, THF, diethyl ether, and mixtures thereof. The reaction temperature is about 25xc2x0 C. to about 100xc2x0 C. and depends on the process chosen. Reaction times are typically about 2 to about 36 hours. In a preferred embodiment, compounds of formula (3) in pyridine at 5xc2x0 C. are treated with para-toluenesulfonyl chloride, warmed to room temperature, and stirred for 16 hours. The products in acetonitrile at 70xc2x0 C. are treated with compounds of formula (4) and potassium carbonate to provide compounds of formula (5-a).
Conversion of compounds of formula (5-a) to compounds of formula (5-b) can be accomplished by treatment of the former with a compound of formula (6) (Y is nitrogen or methine; Q2 is trialkylstannane, boronic acid, boronic ester, magnesium halide, zinc halide, or silyl(alkyl)cyclobutane) and a coupling catalyst. Representative coupling catalysts include Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(dppf)Cl2, Ni(PPh3)4, and Pd(OAc)2. Examples of solvents used in these reactions include THF, water, acetonitrile, dichloromethane, DMF, DME, and mixtures thereof. The reaction temperature is about 25xc2x0 C. to about 120xc2x0 C. and depends on the process chosen. Reaction times are typically about 0.5 to about 36 hours. In a preferred embodiment, compounds of formula (5-a) in THF and water are treated with potassium phosphate and a compound of formula (6) (Y is CH; Q2 is boronic acid), heated to 65xc2x0 C., and stirred for 1 hour to provide compounds of formula (5-b). 
As shown in Scheme 3, compounds of formula (7) can be treated with compounds of formula (4) and base to provide compounds of formula (8). Representative bases include sodium hydroxide, sodium carbonate, potassium carbonate, and lithium hexamethyldisilazide. Examples of solvents used in these reactions include DMSO, water, acetonitrile, THF, and mixtures thereof. The reaction temperature is about xe2x88x9210xc2x0 C. to 50xc2x0 C. and depends on the process chosen. Reaction times are typically 0.5 to 12 hours. In a preferred embodiment, compounds of formula (7) (Q1 is Cl, R4 is alkyl) in DMSO and water at room temperature are treated with a compound of formula (4) (L2 is O and Q1 is Br) and NaOH for 1 hour to provide compounds of formula (8).
Conversion of compounds of formula (8) to compounds of formula (9) can be accomplished by hydrogenation and (Ru2Cl5(R)BINAP2)xe2x88x92Et2NH2+. Examples of solvents used in this reaction include ethanol, methanol, propanol, and tert-butanol. The reaction temperature is about 50xc2x0 C. to 150xc2x0 C. and depends on the process chosen. Reaction times are about 1-24 hours. In a preferred embodiment, compounds of formula (3) in ethanol are treated with (Ru2Cl5(R)BINAP2)xe2x88x92Et2NH2+ and 2M HCl and heated to 100xc2x0 C. under hydrogen for 8 hours to provide compounds of formula (9).
Compounds of formula (9) (R4 is alkyl) can be converted to compounds of formula (10) (R4 is H) by treatment with aqueous base, followed by treatment with aqueous acid. Representative bases include sodium hydroxide, potassiym hydroxide, and lithium hydroxide. Examples of acids used in these reactions are hydrochloric acid, acetic acid, nitric acid, and sulfuric acid. Solvents used in these reactions include isopropanol, isopropanol acetate, ethyl acetate, ethanol, methanol, and mixtures thereof. The reaction temperature is about 0xc2x0 C. to 25xc2x0 C. and depends on the process chosen. Reaction times are typically 10 minutes to 24 hours. In a preferred embodiment, compounds of formula (9) in ethanol at 5xc2x0 C. are treated with aqueous potassium hydroxide over 10 minutes, warmed to room temperature, treated with water and isopropyl acetate, cooled to 5xc2x0 C., and treated with 6M hydrochloric acid to provide compounds of formula (10).
Conversion of compounds of formula (10) to compounds of formula (11) can be accomplished by coupling with an appropriately substituted hydroxylamine and a carbonyl activating group such as DCC, DIC, HOBT, EDCI, and PyBOP, and base. Representative bases include NMM, diisopropylethylamine, and DBU. Examples of solvents used in these reactions include dichloromethane, chloroform, DMF, THF, and NMP. The reaction temperature is about xe2x88x9210xc2x0 C. to 60xc2x0 C. and depends on the process chosen. Reaction times are typically 0.5-24 hours. In a preferred embodiment, compounds of formula (10) in DMF at 5xc2x0 C. are treated with EDCI, HOBT, NMM, and O-benzylhydroxylamine hydrochloride, warmed to room temperature, and stirred for 30 minutes to provide compounds of formula (11).
Compounds of formula (11) can be converted to compounds of formula (12) by treatment with a diazo compound and a triaryl- or trialkylphosphine. Representative diazo compounds include DIAD and DEAD, while representative phosphines include triphenylphosphine and tributylphosphine. Examples of solvents used in these reactions are THF, MTBE, diethyl ether, and DME. The reaction temperature is about 20xc2x0 C. to 70xc2x0 C. and depends on the process chosen. The reaction time is typically 0.5 to 3 hours. In a preferred embodiment, compounds of formula (11) in THF at 40xc2x0 C. are treated with DEAD and triphenylphosphine and stirred for 2 hours to provide compounds of formula (12).
Conversion of compounds of formula (12) to compounds of formula (13) can be accomplished by treatment with an aqueous hydroxide base. Representative bases include sodium hydroxide, lithium hydroxide, and potassium hydroxide. Examples of solvents used in these reactions include toluene, hexanes, benzene, THF, water, and mixtures thereof. The reaction temperature is about 30xc2x0 C. to 80xc2x0 C. and depends on the process chosen. Reaction times are typically 1 to 24 hours. In a preferred embodiment, compounds of formula (12) in toluene are treated with aqueous lithium hydroxide, heated to 60xc2x0 C. for 3 hours, cooled to room temperature, and stirred for 16 hours to provide compounds of formula (13).
Compounds of formula (13) can be converted to compounds of formula (14) by treatment with diphenylphosphoryl azide and base. Representative bases include diisopropylethyl amine, triethylamine, and pyridine. Examples of solvents used in these reactions include THF, diethyl ether, MTBE, and dioxane. The reaction temperature is about 25xc2x0 C. to 100xc2x0 C. and depends on the process chosen. Reaction times are typically 1 to 24 hours. In a preferred embodiment, compounds of formula (13) in THF are treated with diphenylphosphoryl azide and diisopropylethyl amine, heated to reflux, and stirred for 3 hours to provide compounds of formula (14), which cyclize under the reaction conditions to provide compounds of formula (5-c). 
As shown in Scheme 4, compounds of formula (5) can be converted to compounds of formula (15) by treatment with base. Representative bases include potassium hydroxide, sodium hydroxide, and lithium hydroxide. Examples of solvents used in these reactions include water, THF, acetonitrile, and mixtures thereof. The reaction temperature is about 30xc2x0 C. to 120xc2x0 C. and depends on the process chosen. Reaction times are typically 1 to 24 hours. In a preferred embodiment, compounds of formula (5) in water are treated with potassium hydroxide, heated to reflux, and stirred for 9 hours to provide compounds of formula (15). 
As shown in Scheme 5, compounds of formula (15-a) can be converted to compounds of formula (16) by treatment with an appropriately substituted aldehyde (R9CHO). Examples of solvents used in this reaction include toluene, hexanes, heptane, and benzene. The reaction temperature is about 30xc2x0 C. to 120xc2x0 C. and depends on the process chosen. Reaction times are about 1 to 36 hours. In a preferred embodiment, compounds of formula (15-a) in toluene are treated with an aldehyde (R9CHO) and heated to 80xc2x0 C. for 2 hours to provide compounds of formula (16).
Conversion of compounds of formula (16) to compounds of formula (18) can be accomplished by treatment with compounds of formula (17) and a diazo compound and a triaryl- or trialkylphosphine. Representative diazo compounds include DIAD and DEAD, while representative phosphines include triphenylphosphine and tributylphosphine. Examples of solvents used in these reactions are THF, MTBE, diethyl ether, and DME. The reaction temperature is about xe2x88x9210xc2x0 C. to 35xc2x0 C. and depends on the process chosen. Reaction times are typically 0.5 to 12 hours. In a preferred embodiment, compounds of formula (16) in THF at 1xc2x0 C. are treated with compounds of formula (17), DIAD, and triphenylphosphine over 1.25 hours to provide compounds of formula (18).
Compounds of formula (18) can be converted to compounds of formula (19) by treatment with an oxidizing agent. Representative oxidizing agents include m-CPBA, trifluoroperacetic acid, and 2,5-dinitroperoxybenzoic acid. Examples of solvents used in these reactions include MTBE, THF, and diethyl ether. The reaction temperature is about xe2x88x9278xc2x0 C. to 35xc2x0 C. and depends on the process chosen. Reaction times are typically 0.5 to 4 hours. In a preferred embodiment, compounds of formula (18) in THF at xe2x88x9245xc2x0 C. are treated with m-CPBA and warmed to 0xc2x0 C. over 2 hours to provide compounds of formula (19).
Conversion of compounds of formula (19) to compounds of formula (20) can be accomplished by treatment with N-hydroxylamine followed by treatment with aqueous base. Representative bases include sodium hydroxide, potassium hydroxide, and lithium hydroxide. Examples of solvents used in this reaction include water, THF, dioxane, and mixtures thereof. The reaction temperature is about xe2x88x9210xc2x0 C. to 35xc2x0 C. and depends on the process chosen. Reaction times are typically 0.5 to 48 hours. In a preferred embodiment, compounds of formula (19) in THF at 1xc2x0 C. are treated with N-hydroxylamine hydrochloride in water over 1 hour, warmed to room temperature, and stirred for 18 hours to provide compounds of formula (20). 
As shown in Scheme 6, compounds of formula (20-a) can be converted to compounds of formula (20-b) by the procedure described in Scheme 2. 
As shown in Scheme 7, compounds of formula (15-b) can be converted to compounds of formula (22) by treatment with compounds of formula (21). Examples of solvents used in this reaction include THF, diethyl ether, MTBE, and dioxane. The reaction temperature is about 20xc2x0 C. to 40xc2x0 C. and depends on the process chosen. Reaction times are typically 0.5 to 12 hours. In a preferred embodiment, compounds of formula (15-b) in THF at room temperature are treated with compounds of formula (21) and stirred for 0.5 hours to provide compounds of formula (22).
Coversion of compounds of formula (22) to compounds of formula (20-c) can be accomplished by treatment with acid. Representative acids include hydrochloric acid, sulfuric acid, and nitric acid. Examples of solvents used in these reactions include water, THF, dioxane, and mixtures thereof. Reaction times are about 1 to 24 hours. In a preferred embodiment, compounds of formula (22) in THF are treated with 6M HCl, heated to reflux, and stirred for 6 hours to provide compounds of formula (20-c). 
As shown in Scheme 8, compounds of formula (20) can be converted to compounds of formula (23) by treatment with a formylating agent. Representative formylating agents include acetic anhydride/formic acid and 2,2,2-trifluoroethyl formate. Examples of solvents used in these reactions include formic acid, THF, MTBE, and mixtures thereof. The reaction temperature is about 25xc2x0 C. to 65xc2x0 C. and depends on the process chosen. Reaction times are typically 15 minutes to 6 hours. 
As shown in Scheme 9, compounds of formula (23-a), can be converted to compounds of (23-b) by the procedures described in Scheme 2.